It is generally accepted that an elevated serum cholesterol (CH) level (i.e. hyperlipidemia) or, more precisely, an elevated low-density lipoprotein cholesterol (LDL-CH) level, is an important inducement of cerebral apoplexy, coronary heart diseases and myocardial infarction. In addition, hyperlipidemia is also a major risk factor for the development of hypertensive diseases and diabetes mellitus. Hyperlipidemia may further induce hepatic adipose infiltration, hepatic cirrhosis, renal arteriosclerosis, renal failure, gallstone, pancreatitis, subhyaloid hemorrhage, blindness, and cause disorders of male sexual dysfunction, senile dementia, and the like. Recent studies have suggested a potential relationship between hyperlipidemia and onset of some tumors.
The discovery of statins, one of HMG-CoA (3-hydroxy-3-methylglutaryl coenzyme A) reductase inhibitors, in 1970s broke a new path for the development of antihyperlipidemic drugs. Statins have a common active dihydroxy-heptanoic acid moiety that can be hydrolyzed in vivo into a β-hydroxy acid. As the β-hydroxy acid has a chemical structure similar to HMG-CoA, it can competitively bind to HMG-CoA reductase that catalyzes the conversion of HMG-CoA to mevalortic acid, thereby reducing the activity of the reductase, blocking the cholesterol biosynthesis, and promoting the increment of the amount and activity of LDL receptors on the surface of liver cells. Thus, the reduction of a serum LDL cholesterol level is promoted and thus the total serum cholesterol level is reduced so that diseases associated with hyperlipidemia can be treated.
Recent studies have shown that statins possess lots of properties besides adjusting serum cholesterol. The studies of American Cancer Society have shown that statins have activities for preventing and treating acute myeloblastic leukemia, colon carcinoma, breast carcinoma, and carcinoma of head of pancreas. The study of CARE demonstrates that pravastatin can cut down the risk of colon carcinoma by 43%, and the study of 4S demonstrates that simvastatin can cut down the risk of colon carcinoma by 19%. Simvastatin shows a lethal effect to myeloid progenitor cells of both normal people and patients suffering from acute myeloblastic leukemia, and can be used as an ancillary drug in chemotherapy. In a report of Doctor Banke Agarwal of St. Luke's-Roosevelt Hospital center, Colombia University, New York, it is suggested that statins and non steroidal anti-inflammatory drugs (NSAIDs) have synergetic effects on preventing colorectal cancer.
Statins can also be used to treat osteoporosis. Clinical trials on human prove that statins have sclerotin reparation effects at a dosage proposed for treating hyperlipidemia. The mechanism of the effect of statins on osteoporosis lies in the competitive inhibition of HMG CoA reductase, thereby reducing the biosynthesis of cholesterol in liver and its direct metabolite, mevalonate. Meanwhile, researchers have found that mevalonate may have an activity for inhibiting the promoter of bone morphogenetic protein-2 (BMP-2) gene, and this answers why statins have biological effects on bones.
Studies have demonstrated that a long term administration of statins can reduce the risk of cerebral apoplexy by 11-31%. And the study in Loyola University Medical Center, Chicago, Ill. U.S.A, shows that the morbidity of Alzheimer disease in patients taking lovastatin (Mevacor) and pravastatin (Pratchd) is 60-73% lower than those taking other medicaments for treating cardiovascular and cerebrovascular disorders or hypertensive diseases.
Furthermore, the most recent studies have shown that statins have protecting effects on kidney that are independent of their anti-hyperlipidemia properties. The serum concentration of C-active protein (CRP) is lowered in patients taking statins, which demonstrates that a long term administration of statins can cut down the risk of cardiovascular and cerebrovascular disorders by abating inflammations.
There have been a number of references in the art relating to statins compounds and preparation thereof. For example, U.S. Pat. No. 5,034,399 discloses substituted 1,8-naphthyridines as inhibitors of HMG-CoA reductase, their preparation and their use in medicaments.
U.S. Pat. No. 5,011,930 discloses mevalonolactones having a quinoline ring as inhibitors of HMG-CoA reductase, processes for their production and their pharmaceutical uses. All references mentioned above are explicitly incorporated herein by reference in their entirety.